@article {1921, title = {New COL6A6 Variant Causes Autosomal Dominant Retinitis Pigmentosa in a Four-Generation Family.}, journal = {Invest Ophthalmol Vis Sci}, volume = {63}, year = {2022}, month = {2022 Mar 02}, pages = {23}, abstract = {

Purpose: To report that variants in the gene for a large lamina basal component protein, COL6A6 (collagen type VI alpha 6 chain, Col6α6), linked to chromosome 3p22.1 causes retinitis pigmentosa (RP) in patients with autosomal dominant transmission (adRP).

Methods: A positional-cloning approach, whole exome sequencing, and modeling were used. The proband and several affected family members have been phenotyped and followed for over 12 years.

Results: A heterozygous missense variant, c.509C\>G (p. Ser170Cys) in exon 2 of COL6A6 (comprised of 36 exons and 2236 amino acids), was observed in a four- generation family and is likely to cause the adRP phenotype. It was identified in 10 affected members. All affected family members had a distinct phenotype: late-onset rod cone dystrophy, with good retained visual acuity, until their late 70s. Immunohistochemistry of human retina showed a dot-like signal at the base of the inner segments of photoreceptors and outer plexiform layer (OPL). The structural modeling of the N7 domain of Col6α6 suggests that the mutant might result in the abnormal cellular localization of collagen VI or malformation of collagen fibers resulting in the loss of its unique filament structure.

Conclusions: COL6A6 is widely expressed in human tissues and evolutionary conserved. It is thought to interact with a range of extracellular matrix components. Our findings suggest that this form of RP has long-term useful central visual acuity and a mild progression, which are important considerations for patient counseling.

}, keywords = {Collagen Type VI, Cone-Rod Dystrophies, Exons, Humans, Mutation, Missense, Pedigree, Retinitis Pigmentosa}, issn = {1552-5783}, doi = {10.1167/iovs.63.3.23}, author = {Vaclavik, Veronika and Tiab, Leila and Sun, Young Joo and Mahajan, Vinit B and Moulin, Alexandre and Allaman-Pillet, Nathalie and Munier, Francis L and Schorderet, Daniel F} } @article {699, title = {Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0122352}, abstract = {

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G\>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

}, keywords = {Base Sequence, Calpain, Computational Biology, DNA Primers, Female, Fluorescein Angiography, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Retinal Detachment, Sequence Analysis, DNA, Tomography, Optical Coherence, Uveitis, Vitreoretinopathy, Proliferative}, issn = {1932-6203}, doi = {10.1371/journal.pone.0122352}, author = {Bassuk, Alexander G and Yeh, Steven and Wu, Shu and Martin, Daniel F and Tsang, Stephen H and Gakhar, Lokesh and Mahajan, Vinit B} }